Cannabis dependence is a well-recognized syndrome characterized by tolerance and withdrawal for which there are no approved treatments. Several medications have been tested for cannabis withdrawal and/or dependence, but none have been shown to be consistently effective. Substitution treatment with delta-9- tetrahydrocannabinol (THC), while showing some promise in reducing cannabis withdrawal syndrome (CWS), is limited by its psychoactive effects, abuse liability, and by its limited relapse prevention effects An alternative to substitution treatment may be to potentiate the signaling through the endogenous cannabinoid system. Anandamide, a principal endogenous ligand of brain cannabinoid receptors (CB1R) is degraded by the enzyme fatty acid amide hydrolase (FAAH). Recently, a FAAH inhibitor which increases anandamide levels was shown to reduce CWS in THC-dependent animals. Compared to THC or cannabis, FAAH-inhibitors 1) do not have psychoactive effects, 2) are not rewarding, 3) do not increase the abuse liability of other addictive drugs, 4) are not associated with tolerance and 5) produce fewer changes in CB1-R function. PF-04457845 is an orally active, long-acting, potent and selective FAAH inhibitor that does not have psychoactive or cognitive effects, does not have effects suggestive of abuse liability or discontinuation-related withdrawal symptoms and is well-tolerated at the proposed dose. Hypotheses: PF-04457845 will attenuate the subjective, behavioral, polysomnographic, cognitive and endocrine changes associated with cannabis withdrawal syndrome. Furthermore, PF-04457845 will reduce cravings for cannabis and relapse rates in recently abstinent cannabis dependent individuals. Approach: The effects of FAAH inhibition on cannabis withdrawal and relapse will be studied in this proof-of- concept study. Treatment seeking cannabis-dependent subjects (n= 48) with a clear history of CWS will be included in a randomized, double-blind, placebo-controlled study. After a screening period, subjects will be randomized to receive placebo or PF-04457845 (4 mg) provided through an agreement with Pfizer. The treatment phase consists of a 1-week inpatient stay to achieve abstinence and precipitate withdrawal, followed by a 3-week outpatient phase to assess relapse prevention. Innovation: There are no known treatments for cannabis dependence. FAAH inhibitors are a novel class of compounds. There are very few FAAH-inhibitors that are available for use in humans, and none are available commercially. FAAH-inhibitors have not been tested for the treatment of cannabis dependence in humans. Therefore, the proposed study is innovative. PUBLIC HEALTH RELEVANCE: There are no FDA approved treatments for cannabis dependence. The goal of the proposed study is to test the safety and efficacy of a drug that increases the brain's own cannabis-like chemical messenger in reducing cannabis withdrawal syndrome and preventing relapse.